Thermodynamics for the Stabilization of Amorphous Active Pharmaceutical Ingredients via Polymer-Based Formulations

大多数活性药物成分(API)都是非常疏水的，在水介质中的溶解度极低，导致生物利用度非常低。出于这个原因，超过80%的新开发的、有前途的原料药从未成为药物。此外，它们中的大多数是结晶固体，表现出非常缓慢的溶解动力学，因此在它们通过肠道的过程中不能被人体充分吸收。改善溶解度和溶解动力学的一种可能性是原料药的非晶化。这可以例如通过将原料药在聚合物基质中的分子溶解或在聚合物基质上吸附原料药(导致原料药/聚合物配方)来实现。目前，合适的聚合物是通过反复试验找到的，而结果通常不能转移到其他原料药。此外，已知无定形原料药在暴露于湿度时，例如在储存条件下，倾向于在聚合物配方中重新结晶或从聚合物中分离出来。本项目的重点是应用热力学原理系统地研究无定形原料药在聚合物配方中的稳定性。由于适当聚合物的化学成分受到监管机构(如FDA)的限制，该项目将研究聚合物的稳定性能如何通过改变其共聚物组成、构象或三维结构来影响。原料药和聚合物的溶解性和相容性将作为这些聚合物性质的函数进行研究。将首次定量测量原料药和聚合物的无定形相容。此外，还将通过实验和模拟相结合的方法研究湿度对API/聚合物相行为的影响。在无法实现热力学稳定性的情况下(例如，在原料药浓度高于溶解度的情况下)，配方至少可以在低于原料药/聚合物配方的玻璃化转变温度的温度下实现动力学稳定。因此，还将研究玻璃化转变温度以及湿度的影响。为此，将开发一个模型，该模型将首次允许预测支化聚合物的玻璃化转变温度，作为聚合物结构、聚合物半柔性和存在添加剂(原料药或改性剂)的函数。该模型还将允许优化用于原料药配方的3D聚合物网络(气凝胶)的制造。基于对原料药/聚合物配方的相行为和玻璃化转变温度的系统实验和热力学模拟，该项目将为选择最适合在给定温度、湿度和原料药浓度下稳定无定形原料药的适当的聚合物性质提供物理可靠的基础。

Most active pharmaceutical ingredients (APIs) are very hydrophobic and show an extremely low solubility in aqueous media leading to a very low bioavailability. For that reason, more than 80% of the newly-developed, promising APIs never make it into a medicine. Moreover, most of them are crystalline solids exhibiting very slow dissolution kinetics and can therefore not be sufficiently absorbed by the body during their way through the intestinal tract. One possibility to improve both, solubility and dissolution kinetics is the amorphization of the APIs. This can e.g. be achieved via molecular dissolution of the API in a polymer matrix or adsorption of the API at a polymer matrix (leading to API/polymer formulations). Appropriate polymers are today found by trial-and-error procedures whereas the results are usually not transferable to other APIs. Moreover, it is known that amorphous APIs tend to re-crystallize in polymer formulations or to demix from the polymer when exposed to humidity, e.g. under storage conditions. This project focuses on the application of thermodynamic principles to systematically investigate the stabilization of amorphous APIs in polymer-based formulations. Since the chemistry of appropriate polymers is restricted by regulatory authorities (e.g. FDA), the project will investigate, how the stabilizing properties of the polymer can be influenced by changing its copolymer composition, conformation, or 3D-structure. Solubility and miscibility of APIs and polymers will be studied as function of these polymer properties. For the first time, amorphous miscibility of APIs and polymers will be measured quantitatively. Moreover, the influence of humidity on the API/polymer phase behavior will be studied by both, experiments and modeling. In cases, where thermodynamic stability cannot be achieved (e.g. at API concentrations higher than solubility), formulations might at least kinetically be stabilized at temperatures below the glass-transition temperature of the API/polymer formulation. Therefore, also the glass-transition temperature as well as the influence of humidity will be investigated. For that purpose, a model will be developed that will for the first time allow to predict the glass-transition temperature of branched polymers as function of polymer architecture, polymer semi flexibility, and in the presence of additives (APIs or modifiers). This model will also allow optimizing the manufacturing of 3D-polymer networks (aeorogels) used for API formulations. Based on systematic experiments and thermodynamic modeling of both, phase behavior and glass-transition temperature of API/polymer formulations, this project will provide a physically-sound basis to choose appropriate polymer properties which are best suitable to stabilize an amorphous API at given temperature, humidity and API concentration.